HK1060566A1 - Anticholinergic agents that can be used as medicaments and method for the production thereof - Google Patents

Abstract

Diphenylalkanoic acid azabicyclooctane ester quaternary salts are new. They can be prepared via new diphenylalkanoic acid azabicyclooctane esters. diphenylalkanoic acid azabicyclooctane ester quaternary salts of compounds of formula (I) are new: X- = anion; A = group (a), (b) or (c): R1,R2 = 1-4C alkyl optionally substituted with OH or halo; R3-R6 = H; 1-4C alkyl; 1-4C alkoxy; OH; CF3; CN; NO2; or halo; and R7 = H; halo; 1-4C alkyl optionally substituted with halo, OH or 1-4C alkoxy; 1-4C alkoxy; 1-4C haloalkoxy; 1-4C alkyl-CO-O-; 1-4C haloalkyl-CO-O-; or CF3-CO-O-. Independent claims are also included for: (1) preparation of compounds (I); and (2) diphenylalkanoic acid azabicyclooctane ester intermediates of formula (IV);

Description

Anticholinergic agents which can be used as medicaments and method for the production thereof

The invention relates to a general formula1Novel anticholinergic formulations

Wherein A, X-and R¹，R²，R³，R⁴，R⁵，R⁶And R⁷The compounds have the meanings given in the claims and the description, their preparation and their use as medicaments.

Background

Anticholinergic agents can be used for a variety of diseases and have therapeutic effects. Particularly noteworthy for the treatment of asthma or COPD (chronic obstructive pulmonary disease). For the treatment of this disease, anticholinergics with a basic structure of scopine (scopin), scopolenol (Torpenol) or scopine (Tropin) are proposed by WO 92/16528.

The object of WO92/16528 is to prepare an effective formulation for anticholinergic effects with a long lasting activity profile. To solve this task, WO92/16528 discloses scopine, scopolenol or the benzilic acid ester of scopolene.

For the treatment of chronic diseases, it is often desirable to prepare medicaments with a long-lasting effect. In principle, frequent re-administration is not necessary to ensure the concentration of the active substance required for a therapeutic effect in the organism over a longer period of time. In addition, the administration of the active substance at longer time intervals can greatly improve the health of the patient. It is particularly desirable to prepare a therapeutically useful drug which can be administered once daily (single dose). The advantage of once daily dosing makes patients quickly accustomed to taking medications routinely at certain times of the day.

For once-a-day administration, the active substance must meet specific requirements. First, the desired activity should be initiated relatively quickly after administration and ideally should have as constant an effect as possible for a relatively long period of time thereafter. In another aspect, the duration of activity of the agent does not substantially exceed about one day. Ideally, the active substance is shown to have such an active property that once daily administration of the drug containing a therapeutically beneficial dose of the active substance can be controlled.

The scopine, scopolenol and the benzilic acid ester of scopolene disclosed in WO92/16528 do not meet this high requirement. Because of their extremely long duration of action, significantly exceeding the approximately one day period mentioned above, they cannot be used for once-a-day therapeutic administration.

It is therefore an object of the present invention to provide novel anticholinergic agents which, owing to their active properties, can be used for the preparation of medicaments for once-daily administration. It is a further object of the present invention to prepare a compound characterized by a rather rapid entry. It is a further object of the present invention to provide compounds which, after a rapid onset of action, have an action which is as constant as possible over a prolonged period of time thereafter. It is a further object of the present invention to provide a dosage form which is substantially not more than about one day for a duration of its activity in a therapeutically effective dose. Finally, the compounds provided by the present invention have active properties that ensure good control of the therapeutic effect (in other words, the total therapeutic effect is not associated with side effects due to the accumulation of substances in the body).

Detailed description of the invention

It has been found that, surprisingly, the above object is achieved by the general formula1In which R is⁷The radicals are not hydroxyl radicals.

Thus the invention relates to the general formula1Compound (I)

Wherein

A represents a double bond group selected from

And

X^-denotes an anion having a single negative charge,

R¹and R²Is represented by C₁-C₄-an alkyl group which may be optionally substituted by a hydroxyl group or a halogen atom;

R³，R⁴，R⁵and R⁶May be the same or different and each represents hydrogen, C₁-C₄-alkyl radical, C₁-C₄Alkoxy, hydroxy, CF₃，CN，NO₂Or a halogen atom;

R⁷represents hydrogen, C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Alkylene-halogen atoms, halogen atoms-C₁-C₄-alkoxy radical, C₁-C₄alkylene-OH, CF₃，-C₁-C₄alkylene-C₁-C₄-alkoxy, -O-COC₁-C₄-alkyl, -O-C₁-C₄-alkyl-halogen atoms, -O-COCF₃Or a halogen atom,

but do not

If A representsWhen the temperature of the water is higher than the set temperature,

R¹and R²Represents a methyl group and

R³，R⁴，R⁵and R⁶Represents hydrogen, and is represented by the formula,

and R is⁷Not both may be hydrogen.

Preferably of the formula1The compound is

Wherein

A represents a double bond group selected from

And

X^-denotes an anion with a single negative charge selected from chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate, preferably bromide,

R¹and R²Each of which may be the same or different, represents a group selected from methyl, ethyl, n-propyl and isopropyl, optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R³，R³，R⁵and R⁶May be the same or different and each represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, fluoro, chloro, bromo, CN, CF₃Or NO₂；

R⁷Represents hydrogen, methyl, ethyl, methoxy, ethoxy, -CH₂-F，-CH₂-CH₂-F，-O-CH₂-F，-O-CH₂-CH₂-F，-CH₂-OH，-CH₂-CH₂-OH，CF₃，-CH₂-OMe，-CH₂-CH₂-OMe，-CH₂-OEt，-CH₂-CH₂-OEt，-O-COMe，-O-COEt，-O-COCF₃，-O-COCF₃Fluorine, chlorine or bromine.

Particularly preferred are compounds of the formula1The compound is:

wherein

A represents a double bond group selected from

And

X^-denotes an anion with a single negative charge, selected from chloride, bromide and methanesulfonate, preferably bromide,

R¹and R²May be the same or different and each represents a group selected from methyl and ethyl, optionally substituted by hydroxy or fluoro, preferably unsubstituted methyl;

R³，R³，R⁵and R⁶May be the same or different and each represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, fluoro, chloro or bromo;

R⁷represents hydrogen, methyl, ethyl, methoxy, ethoxy, CF₃Or fluorine.

Preferred formulae according to the invention1The compound is as follows

A represents a double bond group selected from

And

X^-represents a bromide anion;

R¹and R²May be the same or different and each represents a group selected from methyl and ethyl, preferably methyl;

R³，R³，R⁵and R⁶Can be the same as orDifferent, each represents hydrogen, methyl, methoxy, chlorine or fluorine;

R⁷represents hydrogen, methyl or fluorine.

Of particular interest according to the invention are the formulae1The compound is as follows

A represents a double bond group selected from

And

X^-represents a bromide ion;

R¹and R²Each independently of the other, represents a methyl or ethyl group, preferably a methyl group;

R³，R³，R⁵and R⁶May be the same or different and each represents hydrogen or fluorine, preferably hydrogen;

R⁷represents hydrogen, methyl, or fluorine, preferably methyl or fluorine and most preferably methyl.

The invention relates to1The compounds, if desired, are in the form of individual optical isomers, mixtures of individual enantiomers or racemic mixtures.

General formula (VII)1In the compound R³，R⁴，R⁵And R⁶Radicals other than hydrogen may be referred to as "-C-R⁷The "radical bonds" are located in the ortho, meta or para positions. If R is³，R⁴，R⁵And R⁶None of the radicals represents hydrogen, then R³And R⁵Preferably bonded in the para position and R⁴And R⁶Preferably, the linkage is in the ortho or meta position and is most preferably in the meta position. If R is³And R⁴One of the radicals and R⁵And R⁶One of the radicals represents hydrogen, the other radical in each case preferably being bonded in the meta or para position, most preferablyThe para position is preferred. If R is³，R⁴，R⁵And R⁶None of the radicals is hydrogen, then the general formula according to the invention1A compound wherein R³，R⁴，R⁵And R⁶Particularly preferred are those having the same definition.

Of particular interest according to the invention are the formulae1A compound wherein the ester substituent is alpha to the nitrogen-bicyclic group. The compounds correspond to the general formula1-α

The following compounds are of particular importance according to the invention:

-tropenol 2, 2-diphenylpropionate-methyl bromide;

-scopine 2, 2-diphenylpropionate-methyl bromide;

-scopine 2-fluoro-2, 2-diphenylacetate-methyl bromide;

-tropenol 2-fluoro-2, 2-diphenylacetate-methyl bromide;

unless otherwise specified, an alkyl group is a straight or branched chain radical containing 1 to 4 carbon atoms. For example: methyl, ethyl, propyl or butyl. The abbreviations Me, Et, Prop or Bu are used in some cases for methyl, ethyl, propyl or butyl, respectively. Unless otherwise indicated, the definition of propyl and butyl includes all possible isomeric forms of these groups. Thus, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, and the like.

Unless otherwise specified, alkylene groups are branched and straight-chain double-bonded alkyl bridges containing from 1 to 4 carbon atoms. For example: methylene, ethylene, propylene or butylene.

Unless otherwise indicated, alkylene-halo groups are branched and straight-chain, doubly-bound alkyl bridges containing from 1 to 4 carbon atoms and are mono-, di-or trisubstituted, and preferably monosubstituted, by halogen atoms. Unless otherwise specified, alkylene-OH groups are branched and straight-chain double-bonded alkyl bridges of 1 to 4 carbon atoms which are mono-, di-or trisubstituted and preferably monosubstituted by hydroxyl groups.

Unless otherwise indicated, alkoxy represents branched and straight chain alkyl groups containing 1 to 4 carbon atoms bonded through an oxygen atom. Examples include: methoxy, ethoxy, propoxy or butoxy. The abbreviations MeO-, EtO-, PropO-or BuO-are used in some cases to denote methoxy, ethoxy, propoxy or butoxy. Unless otherwise indicated, the definition of propoxy and butoxy includes all possible isomeric forms of these groups. Thus, for example, propoxy includes n-propoxy and isopropoxy, and butoxy includes isobutoxy, sec-butoxy and tert-butoxy, and the like. Sometimes, within the scope of the present invention, the term alkoxy is used instead of alkyloxy. Thus methoxy, ethoxy, propoxy or butoxy also denotes methyloxy, ethyloxy, propyloxy or butyloxy.

Unless otherwise indicated, alkylene-alkoxy denotes branched and straight-chain doubly-bonded alkyl bridges of 1 to 4 carbon atoms which are mono-, di-or trisubstituted by an alkoxy group and are preferably monosubstituted.

Thus, unless otherwise indicated, -O-CO-alkyl represents branched and straight-chain alkyl groups containing 1 to 4 carbon atoms linked by ester groups. The alkyl group is directly bonded to the carbonyl carbon of the ester group. The meaning of-O-CO-alkyl-halo is also meant. -O-CO-CF₃It represents trifluoroacetate.

Halogen atoms within the scope of the present invention denote fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine and bromine are preferred halogen atoms. The CO group represents a carbonyl group.

The compounds of the invention can be prepared analogously to the known procedures of the prior art as described in the following part of the description (scheme 1). Formula (II)3The carboxylic acid derivatives are known in the art or can be prepared using synthetic methods known in the art. If only passed through properlySubstituted carboxylic acids are known in the art, of the formula3The compounds can also be prepared directly from these compounds by acid-or base-catalyzed esterification using the corresponding alcohols, or by halogenation using the corresponding halogenating agents.

Reaction scheme 1:

starting from2A compound of the formula4Can be reacted with a compound of formula (II)3Obtained by direct reaction of carboxylic acid derivatives, in which R represents, for example, chlorine or C₁-C₄-alkoxy groups. When R represents C₁-C₄In the case of alkoxy groups, this reaction can be carried out, for example, in a sodium melt at elevated temperatures, preferably at from about 50 to 150 ℃ and optimally at from about 90 to 100 ℃ and at low pressures, preferably below 500 mbar (mbar, 1 mbar to 100 pascals) and optimally below 75 mbar. Alternative derivatives 3 in which R represents C₁-C₄Alkoxy, the corresponding acid chloride (R represents Cl) may be used.

Thus obtained formula4The compounds can be prepared by reacting with a compound wherein R is²And X is as defined above²By reaction of-X to form1A target compound. This synthesis step can also be carried out analogously to the synthesis example disclosed in WO 92/16528.

Except that the synthetic formula illustrated in reaction scheme 14In addition to the procedure for compounds in which the nitrogen bicyclic group is a scopine derivative, derivative 4 can be obtained by oxidation (epoxidation). Wherein the nitrogen-bicyclic group is an scopolenyl group4A compound is provided. This reaction can be carried out according to the invention as follows.

Compound 4, wherein a represents-CH ═ CH-is suspended in a polar organic solvent, preferably in a solvent selected from N-methyl-2-pyrrolidinone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then heated at a temperature of about 30-90 ℃, preferably 40-70 ℃. The appropriate oxidizing agent is then added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. The oxidant is vanadium pentoxide mixed with hydrogen peroxide, preferably hydrogen peroxide-urea complex combined with vanadium pentoxide. The mixture is processed in the usual manner. The product is purified by crystallization or chromatography depending on the tendency to crystallize.

In addition, wherein R⁷Represents a halogen atom of the formula4The compounds can also be obtained by reacting the process shown in FIG. 2.

Reaction scheme 2:

here is of the formula5Benzohydrolates are converted to R therein using a suitable halogenating agent⁷Represents a halogen atom of the formula4A compound is provided. Halogenation reactions carried out according to reaction scheme 2 are well known in the art.

Formula (II)5The benzilic acid esters of (a) can be obtained according to methods known in the art or analogous methods (cf. for example WO 92/16528).

As shown in reaction scheme 1, of the general formula4The intermediate products of (a) have a critical significance. Thus in another aspect, the invention relates to4Intermediate product

Wherein

A represents a double bond group selected from

And

R¹is represented by C₁-C₄-an alkyl group, which may be optionally substituted by a hydroxyl group or a halogen atom;

R³，R⁴，R⁵and R⁶May be the same or different and each represents hydrogen, C₁-C₄-alkyl radical, C₁-C₄Alkoxy, hydroxy, CF₃，CN，NO₂Or a halogen atom;

R⁷represents hydrogen, C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₄Alkylene-halogen atoms, halogen atoms-C₁-C₄-alkoxy radical, C₁-C₄-alkylene-OH-, CF₃，-C₁-C₄alkylene-C₁-C₄-alkoxy, -O-COC₁-C₄-alkyl, -O-C₁-C₄-alkyl-halogen atoms, -O-COCF₃Or a halogen atom,

but do not

If A represents

R¹Represents a methyl group and

R³，R⁴，R⁵and R⁶Represents hydrogen, and is represented by the formula,

then R is⁷Is not n-propyl.

Preferably of the formula4The compound is

Wherein

A represents a double bond group selected from

And

R¹each of which is the same or different and represents a group selected from methyl, ethyl, n-propyl and isopropyl, optionally substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R³，R⁴，R⁵and R⁶May be the same or different and each represents hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, fluoro, chloro, bromo, CN, CF₃Or NO₂；

R⁷Represents hydrogen, methyl, ethyl, methoxy, ethoxy, -CH₂-F，-CH₂-CH₂-F，-O-CH₂-F，-O-CH₂-CH₂-F，-CH₂-OH，-CH₂-CH₂-OH，CF₃，-CH₂-OMe，-CH₂-CH₂-OMe，-CH₂-OEt，-CH₂-CH₂-OEt，-O-COMe，-O-COEt，-O-COCF₃，-O-COCF₃Fluorine, chlorine or bromine.

Particularly preferred are compounds of the formula4A compound which is a mixture of a compound having a structure,

wherein

A represents a double bond group selected from

And

R¹may be the same or different and each represents a group selected from methyl and ethyl, which may be optionally substituted with hydroxy or fluoro, preferably unsubstituted methyl;

R³，R⁴，R⁵and R⁶Can be the same or different and respectively represent hydrogen, methyl, ethyl, methoxy and ethoxyHydroxy, fluoro, chloro or bromo;

R⁷represents hydrogen, methyl, ethyl, methoxy, ethoxy, CF₃Or fluorine.

Preferred formulae according to the invention4The compound is as follows

A represents a double bond group selected from

And

R¹may be the same or different and each represents a group selected from methyl and ethyl, preferably methyl;

R³，R⁴，R⁵and R⁶May be the same or different and each represents hydrogen, methyl, methoxy, ethoxy, chlorine or bromine;

R⁷represents hydrogen, methyl or fluorine.

Of particular interest according to the invention are compounds of the formula1A compound of which

A represents a double bond group selected from

And

R¹which may be identical or different, represent a methyl or ethyl group, respectively, preferably a methyl group;

R³，R⁴，R⁵and R⁶May be the same or different and each represents hydrogen or fluorine, preferably hydrogen;

R⁷represents hydrogen, methyl, or fluorine, preferably methyl orFluorine and most preferably methyl.

In the same way1A compound of formula4In the intermediate, R³，R⁴，R⁵And R⁶The radicals, if not hydrogen, may be in the ortho, meta or para position relative to the bonds of the "-C-OH" groups. If R is³，R⁴，R⁵And R⁶None of the radicals represents hydrogen, then R³And R⁵Preferably bonded in the para position and R⁴And R⁶Preferably linked in ortho or meta position and most preferably in meta position. Radical R³And R⁴One of the radicals and R⁵And R⁶One of the radicals represents hydrogen, the other radical in each case is preferably bonded in the meta or para position, most preferably in the para position. If R is³，R⁴，R⁵And R⁶None of the radicals represents hydrogen, then the formula according to the invention4A compound of formula (I) wherein R³，R⁴，R⁵And R⁶Those having the same definition are particularly preferable.

The synthesis examples described hereinafter serve to further illustrate the invention. But merely as an example of a procedure to illustrate the invention and not to limit the invention to the illustrated subject matter.

Example 1: scopine 2, 2-diphenylpropionate-methyl bromide:

1.1.: 2, 2-diphenylpropionyl chloride 3 a:

52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwise at 20 ℃ to a suspension of 25.0 g (0.11 mol) of 2, 2-diphenylpropanoic acid in dichloromethane (100 ml) and 4 drops of dimethylformamide. The mixture was stirred at 20 ℃ for 1 hour and at 50 ℃ for 0.5 hour. The solvent was distilled off, and the residue left behind was used in the next step without further purification.

1.2.: scopine 2, 2-diphenylpropionate 4 a:

step 1.1. the resulting residue was dissolved in 100 ml of dichloromethane and 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane were added dropwise at 40 ℃. The suspension obtained is stirred for 2 hours at 40 ℃ and the precipitate formed is then filtered off with suction and the filtrate is extracted first with water and then with aqueous hydrochloric acid. The combined aqueous phases are made alkaline with aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase is dehydrated over sodium sulfate, evaporated to dryness and the hydrochloride salt is precipitated from the residue. The product was purified from acetonitrile by recrystallization.

Yield: 20.85 g (═ 47% of theory)

TLC: rf value: 0.24 (eluent: sec-butanol/formic acid/water 75: 15: 10);

melting point: 203 ℃ to 204 DEG C

1.3.: scopine 2, 2-diphenylpropionate-methyl bromide:

11.98 exempt (0.033 mole)4a210 ml of acetonitrile, 70 ml of dichloromethane and 20.16 g (0.1 mol) of 46.92% methyl bromide were mixed in acetonitrile at 20 ℃ and left to stand for 3 days. The solution was evaporated to dryness and the residue was recrystallized from isopropanol.

Yield: 11.34 grams (═ 75% theoretical); melting point: 208 ℃ and 209 ℃.

C₂₄H₂₈NO₃×Br(458.4)；

Elemental analysis: calculated values: c (62.89) H (6.16) N (3.06)

Measured value: c (62.85) H (6.12) N (3.07).

Example 2: scopine 2-fluoro 2, 2-diphenylacetate-methyl bromide:

2.1.: scopine benzilate 5 a:

the preparation of scopine benzilic acid esters is known from the prior art. Described in WO 92/16528.

2.2.: scopine 2-fluoro-2, 2-diphenylacetate 4 b:

a solution of 2.66 g (0.02 mol) of dimethylaminosulfur trifluoride in 10 ml of dichloromethane was cooled to 0 ℃ and 5.48 g (0.015 mol) of scopine benzilate were added dropwise5aIn 100 ml of dichloromethane. The mixture was then stirred for a further 30 minutes at 0 ℃ and for a further 30 minutes at 20 ℃. On cooling the solution was mixed with water, sodium bicarbonate was added (to pH 7-8) and the organic phase was separated. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water, dried over sodium sulfate and evaporated to dryness. The hydrochloride salt precipitated from the residue and recrystallized from acetonitrile.

Yield: 6.90 g (═ 85% of theory)

Melting point: 227-.

2.3.: scopine 2-fluoro-2, 2-diphenylacetate-methyl bromide:

2.88 g (0.0078 mol) of scopine benzilic acid ester as free base were reacted in a similar procedure to step 1.3. The product was purified by recrystallization from isopropanol. Yield: 2.62 g (═ 73% of theory);

TLC: rf value: 0.31 (eluent same as step 1.2); melting point: 130 ℃ and 134 ℃.

Example 3: tropenol 2, 2-diphenylpropionate-methyl bromide:

3.1.: methyl 2, 2-diphenylpropionate 3 b:

37.60 g (0.247 mol) of DBU are added dropwise at 20 ℃ to a suspension of 50.8 g (0.225 mol) of 2, 2-diphenylpropanoic acid and 200 ml of acetonitrile. 70.10 g (0.494 mol) of methyl iodide were added dropwise to the resulting solution over 30 minutes. The mixture was then stirred at 20 ℃ overnight. The solvent was removed by evaporation and the residue was extracted with ether/water. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness.

Yield: 48.29 g of viscous residue 32(═ 89% of theory)

3.2: tropenol 2, 2-diphenylpropionate 4 c:

4.80 g (0.02 mol) methyl 2, 2-diphenylpropionate3b2.78 g (0.02 mol) of tropenol and 0.046 g of sodium in the melt are heated in a boiling water bath at 75 mbar for 4 hours, occasionally with shaking. After cooling, the sodium residue was dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dihydromethane/water. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness.

From the residue of the process, the residue is,4cprecipitated as the hydrochloride salt and recrystallized from acetone.

Yield: 5.13 g (═ 67% of theory)

TLC: rf value: 0.28 (eluent: sec-butanol/formic acid/water 75: 15: 10);

melting point: 134 ℃ and 135 ℃.

3.3.: tropenol 2, 2-diphenylpropionate-methyl bromide:

2.20 g (0.006 mol)4cThe reaction was carried out in a similar manner to example 1, step 1.3. The crystals formed were filtered off with suction, washed with dichloromethane, dehydrated and then recrystallized from methanol/diethyl ether.

Yield: 1.84 grams (═ 66% theoretical);

TLC: rf value: 0.11 (eluent same as step 1.2); melting point: 222 ℃ and 223 ℃.

C₂₄H₂₈NO₃×Br(442.4)；

Elemental analysis: calculated values: c (65.16) H (6.38) N (3.17)

Measured value: c (65.45) H (6.29) N (3.16).

Example 4: tropenol 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetate-methyl bromide:

4.1.: 3, 3 ', 4, 4' -tetrafluorobenzilic acid ethyl ester 3 c:

grignard reagent (Grignard reagent) was prepared from 2.24 g (0.092 mol) of magnesium turnings, small particle iodine and 17.80 g (0.092 mol) of 1-bromo-3, 4-difluoro-benzene in 100 ml of THF at 50 ℃. After the halide had been added in its entirety, the mixture was stirred for a further 1 hour. The Grignard reagent thus obtained was added dropwise to a solution of 18.81 g (0.088 mol) of ethyl 3, 4-difluorophenyl glycolate in 80 ml of THF at 10 ℃ to 15 ℃ and the resulting mixture was stirred at 5 ℃ for 2 hours. The white suspension is poured into ice/sulfuric acid for subsequent work-up, extracted with ethyl acetate, and the organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by column chromatography (eluent: toluene).

Yield: 10.80 g of oil 1(═ 38% of theory).

4.2.: tropenol 3, 3 ', 4, 4' -tetrafluorobenzilate 5 b:

4.27 g (0.013 mol) of ethyl 3, 3 ', 4, 4' -tetrafluorobenzilic acid 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g of sodium in the melt are heated in a boiling water bath at 75 mbar for 4 hours with occasional shaking. After cooling, the sodium residue was dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dihydromethane/water. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness.

The residue which remains is mixed with 1: 9 diethyl ether/petroleum ether, filtered off with suction and washed.

Yield: 2.50 g (═ 46% of theory)

TLC: rf value: 0.29 (eluent: sec-butanol/formic acid/water 75: 15: 10);

melting point: 147 ℃ and 148 ℃.

4.3.: tropenol 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetate 4 d:

2.66 g (0.012 mol) of bis- (2-methoxyethyl) aminosulfur trifluoride are placed in 10 ml of dichloromethane and 0.01 mol of sulfur is added dropwise at 15-20 ℃ over 20 minutes5bIn 65 ml of a solution of dihydromethane.

The mixture was stirred at ambient temperature for 20 hours, cooled to 0 ℃ and 80 ml of water were carefully mixed with thorough stirring. The mixture is then carefully adjusted to pH 8 with aqueous sodium hydrogencarbonate solution, the organic phases are separated, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over magnesium sulfate and evaporated to dryness. The hydrochloride salt precipitated out and was recrystallized from acetonitrile/diethyl ether.

Yield: 2.60 g white crystals (═ 57% of theory);

melting point: 233 deg.C.

4.4: tropenol 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetate-methyl bromide:

2.20 g (0.0052 mol)4dThe reaction was carried out in a similar manner to example 1, step 1.3. The resulting crystals were filtered off with suction, washed with dichloromethane, dehydrated and then recrystallized from methanol/diethyl ether.

Yield: 1.95 g (═ 72% of theory);

TLC: rf value: 0.17 (eluent: n-butanol/water/formic acid (concentrated)/acetone/dichloromethane 36: 15: 5); melting point: 247 deg.C

C₂₃H₂₁F₅NO₂×Br(518.3)；

Elemental analysis: calculated values: c (53.30) H (4.08) N (2.70)

Measured value: c (53.22) H (4.19) N (2.69).

Example 5: scopine-2, 2-diphenylpropionate-ethyl bromide:

1.81 g (0.005 mol)4a35 ml of acetonitrile and 1.64 g (0.015 mol) of ethyl bromide were mixed at 20 ℃ and left for 3 days. The solution was evaporated to dryness and the residue was recrystallized from ethanol.

Strict rate: 1.38 g (═ 58% of theory); melting point: 208 ℃ and 209 ℃.

TLC: rf value: 0.33 (eluent same as step 1.2); melting point: 210 ℃ and 211 ℃.

C₂₅H₃₀F₅NO₃×Br(472.42)；

Elemental analysis: calculated values: c (63.56) H (6.40) N (2.96)

Measured value: c (63.49) H (6.24) N (2.88).

Example 6: scopine 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetate-methyl bromide:

6.1.: scopine 3, 3 ', 4, 4' -tetrafluorobenzilic acid ester 5 c:

3.61 g (0.011 mol) of ethyl 3, 3 ', 4, 4' -tetrafluorobenzilate3c1.71 g (0.011 mol) of scopine and 0.03 g of sodium in the melt are heated in a boiling water bath at 75 mbar for 4 hours, occasionally shaking. After cooling, the sodium residue was dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness.

The residue which remains is taken up in 1: 9 diethyl ether/petroleum ether, filtered off with suction and washed.

Yield: 1.75 g (═ 36% of theory);

melting point: 178 ℃ and 179 ℃.

6.2.: scopine 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetate 4 e:

0.6 ml (0.0033 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride and 1.2 g (0.0028 mol)5cThe reaction was carried out in a similar manner to example 4, step 4.3.

Yield: 1.15 g of a colourless oil (═ 95% of theory)

6.3.: scopine 2-fluoro-2, 2-bis (3, 4-difluorophenyl) acetate-methyl bromide:

1.15 g (0.0026 mol)4eAnd 1.5 g (0.0079 mol) of 50% methyl bromide solution were reacted in a similar manner to step 1.3 of example 1. The crystals formed were filtered off with suction, washed with dichloromethane, dehydrated and then recrystallized from acetone.

Yield: 0.88 g (═ 63% of theory)

TLC: rf value: 0.27 (eluent: n-butanol/water/formic acid (concentrated)/acetone/dichloromethane 36: 15: 5); melting point: 212 deg.C.

C₂₃H₂₁F₅NO₃×Br(535.33)；

Example 7: tropenol 2-fluoro 2, 2-bis (4-fluorophenyl) acetate-methyl bromide:

7.1.: 4, 4' -Difluorodiphenyl glycolic acid methyl ester 3 d:

7.1.1.: 4, 4' -Difluorodimandelic acid

A solution of 24.62 g (0.1 mol) of 4, 4' -difluorobenzil in 250 ml of dioxane was added dropwise to a flake of 49.99 g (1.25 mol) sodium hydroxide in 300 ml of aqueous solution at about 100 ℃ and stirred for 2 hours. The dioxane was largely distilled off and the remaining aqueous solution was extracted with dichloromethane. When the aqueous solution is acidified with sulfuric acid, the precipitate formed is filtered off with suction, washed and dewatered. The filtrate was extracted with dichloromethane, the organic phase was dried over sodium sulfate and evaporated to dryness.

Yield: 25.01 g (═ 95% of theory); melting point: 133 ℃ C. & 136 ℃ C. (B.)

7.1.2.: 4, 4' -Difluorodiphenyl glycolic acid methyl ester

25.0 g (0.095 mol) of 4, 4' -difluorobenzilic acid was added to a sodium ethoxide solution freshly prepared from 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20 ℃ and stirred for 3 hours. The solution was evaporated to dryness and the residue was dissolved in DMF and 22.57 g (0.16 mol) of methyl iodide was added dropwise at 20 ℃ and the mixture was stirred for 24 hours. By analogous compounds3bThe subsequent treatment and purification are carried out in the manner described.

Yield: 21.06 g 11(═ 80% of theory)

7.2.: tropenol 4, 4' -bisFluorodiphenylacetate 5 d:

11.13 g (0.04 mol) of ethyl 4, 4' -difluorobenzilic acid3dAnd 5.57 g (0.04 mol) of tropenol reacted with 0.09 g of sodium in a manner analogous to that of example 3, step 3.2. The product was recrystallized from acetonitrile.

Yield: 10.43 g (═ 62% of theory);

melting point: 233-.

7.3: tropenol 2-fluoro-2, 2-bis (4-fluorophenyl) -acetate 4 f:

2.94 g (0.013 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride and 3.85 g (0.01 mol)5dIn analogy to example 4, step 4.3 was reacted with 100 ml of dichloromethane. The product was recrystallized from acetonitrile as the hydrochloride salt.

Yield: 2.93 g (═ 69% of theory).

7.4: tropenol 2-fluoro-2, 2-bis (4-fluorophenyl) acetate-methyl bromide:

2.6 g (0.0067 mol)4fAnd 1.9 g (0.0079 mol) of a 50% methyl bromide solution were reacted in a similar manner to step 1.3 of example 1. The resulting crystals were filtered off with suction, washed with dichloromethane, dehydrated and then recrystallized from methanol/diethyl ether.

Yield: 2.82 g of white crystals (═ 87% of theory)

TLC: rf value: 0.55 (eluent: according to example 1, step 1.2);

melting point: 230 ℃ and 231 ℃.

C₂₃H₂₃F₃NO₂×Br(482.34)；

Elemental analysis: calculated values: c (57.27) H (4.81) N (2.90)

Measured value:^C(57.15)H(4.84)N(2.96)。

example 8: scopine 2-fluoro 2, 2-bis (4-fluorophenyl) acetate-methyl bromide:

8.1.: scopine-4, 4' -difluorobenzilic acid ester 5 e:

4.22 g (0.01 mol) of tropenol-4, 4' -difluorobenzil glycolate5dSuspended in 80 ml of DMF. At an internal temperature of about 40 ℃ 2.57 g (0.0273 mol) of hydrogen peroxide-urea in 20 ml of water and 0.2 g (0.0011 mol) of vanadium- (V) oxide were added and the mixture was stirred at 60 ℃ for 4.5 hours. After cooling to 20 ℃ the precipitate formed is filtered off with suction, the filtrate is adjusted to pH3 with 4N hydrochloric acid and sodium thiosulfate is mixed and dissolved in water. The resulting green solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The acidic aqueous phase is made alkaline with sodium carbonate, extracted with dichloromethane and the organic phase is dehydrated with sodium sulfate and concentrated.

Then 0.5 ml of acetyl chloride was added at about 15 ℃ and stirred for 1.5 hours. After extraction with 0.1N hydrochloric acid, the aqueous phase is made basic, extracted with dichloromethane, the organic phase is dehydrated over sodium sulfate and evaporated to dryness to give the hydrochloride salt, which is precipitated from the residue and recrystallized from methanol/diethyl ether.

Yield: 3.61 g white crystals (═ 78% of theory);

melting point: 243 and 244 ℃.

8.2.: scopine 2-fluoro-2, 2-bis (4-fluorophenyl) acetate 4 g:

1.48 g (0.0067 mol) bis- (2-methoxyethyl) aminosulfur trifluoride and 2.0 g (0.005 mol)5eThe reaction was carried out in 80 ml of dichloromethane in a similar manner to example 4, step 4.3. The product was recrystallized from ethanol as the hydrochloride salt.

Yield: 2.07 g (═ 94% of theory); melting point: 238 ℃ and 239 ℃.

8.3.: scopine 2-fluoro-2, 2-bis (4-fluorophenyl) acetate-methyl bromide:

1.6 g (0.004 mol)4gAnd 1.14 g (0.0079 mol) of 50% methyl bromide solution were reacted in a similar manner to step 1.3 of example 1. The resulting crystals were suction filtered, washed with dichloromethane, dehydrated and then recrystallized from acetonitrile.

Yield: 1.65 g of white crystals (═ 61% of theory)

TLC: rf value: 0.25 (eluent: step 1.2 according to example 1);

melting point: 213-214 ℃.

C₂₃H₂₃F₃NO₃×Br(498.34)；

Elemental analysis: calculated values: c (55.43) H (4.65) N (2.81)

Measured value: c (54.46) H (4.67) N (2.80).

Example 9: tropenol 2-fluoro-2, 2-diphenylacetate-methyl bromide:

9.1: tropenol dibenzoacetate 5 f:

tropenol dibenzoate and its preparation are known from WO 92/16528.

9.2: tropenol 2-fluoro-2, 2-diphenylacetate 4 h:

15.86 ml (0.086 mol) of bis- (2-methoxyethyl) aminosulfur trifluoride and 25 g (0.072 mol)5fIn a manner analogous to example 4, step 4.3, at 480 ml of chloroform. The product was recrystallized from acetone as its hydrochloride salt. Yield: 18.6 g white crystals (═ 67% of theory);

melting point: 181 ℃ and 182 ℃.

9.3: tropenol 2-fluoro-2, 2-diphenylacetate-methyl bromide:

11.12 g (0.032 mol)4hAnd 18.23 g (0.096 mol) of a 50% methyl bromide solution were reacted in a similar manner to step 1.3 of example 1. The resulting crystals were recrystallized from acetonitrile.

Yield: 11.91 g white crystals (═ 83% of theory);

TLC: rf value: 0.4 (eluent: step 4.4 according to example 4);

melting point: 238 ℃ and 239 ℃.

C₂₃H₂₅FNO₂×Br(446.36)；

Elemental analysis: calculated values: c (61.89) H (5.65) N (3.14)

Measured value: c (62.04) H (5.62) N (3.17).

Example 10: tropenol 2-fluoro-2, 2- (3-chlorophenyl) acetate-methyl bromide:

10.1: 3, 3' -dichloro benzilic acid methyl ester 3 e:

10.1.1.: 3, 3' -dichlorobenzil:

100 ml of ethanol are taken at ambient temperature and 50.0 g (0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide are added. 10.7 g (0.11 mol) triethanolamine were then added dropwise. The mixture was refluxed for 3 hours and evaporated to dryness. The residue was taken up in ethyl acetate and extracted with water, a solution of sodium metabisulphite in water and a solution of sodium carbonate. Dried over magnesium sulfate and evaporated to dryness. The product obtained is recrystallized from isopropanol and petroleum ether.

Yield: 13.2 g white crystals (═ 13% of theory); melting point: 69-70 ℃.

13.0 g of the Acyloin (Acyloin) thus prepared were dissolved in 460 ml of acetonitrile at room temperature, 0.0867 g of vanadium (V) oxytrichloride were added and oxygen was introduced. After 1.5 hours, the solution was evaporated to dryness, extracted with ethyl acetate and water and sodium carbonate solution, dehydrated over magnesium sulphate and evaporated to dryness. The remaining residue was stirred with petroleum ether/ethyl acetate 95: 5.

Yield: 12.59 g yellow crystals (═ 97% of theory); melting point: 116 ℃ and 117 ℃.

10.1.2.: 3, 3' -dichlorobenzilic acid:

51.45 g (1.286 mol) of sodium hydroxide are placed in 1000 ml of water in a boiling water bath and stirred thoroughly, a solution of 28.5 g (0.102 mol) of 3, 3' -dichlorobenzil in 700 ml of dioxane is added dropwise and the mixture is stirred for a further 1 hour. After cooling, the dioxane was evaporated off, the residue was diluted with water and extracted with diethyl ether. The organic phase is acidified, extracted with dichloromethane, dehydrated over magnesium sulphate and evaporated to dryness.

Yield: 32.7 g (═ 71% of theory)

10.1.3.: 3, 3' -dichlorobenzilic acid methyl ester:

a sodium ethoxide solution was prepared from 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, to which a solution of 26.6 g (0.0855 mol) of 3, 3' -dichlorobenzilic acid in 50 ml of ethanol was added dropwise. The mixture was then stirred at ambient temperature for 4 hours. After the solvent was distilled off, the residue was dissolved in 150 ml of DMF and 24.27 g (0.171 mol) of methyl iodide was added dropwise, followed by stirring for further 24 hours. 300 ml of water and 200 ml of diethyl ether are added dropwise with ice cooling, the phases are separated, the aqueous phase is extracted with diethyl ether, and the organic phase is washed with sodium carbonate solution and shaken with water until neutral. After dehydration over sodium sulfate, the mixture was evaporated to dryness.

Yield: 22.91 g of yellow oil (═ 82% of theory)

10.2.: 5g of tropenol 3, 3' -dichlorobenzilic acid ester:

22.9 g (0.074 mol) of methyl 3, 3' -dichlorobenzilic acid3e15.37 g (0.11 mol) of tropenol and 0.17 g of sodium in the form of a melt are heated in a boiling water bath at 75 mbar for 4 hours with occasional shaking. After cooling, the sodium residue was dissolved in acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness.

The product was recrystallized from acetonitrile in its hydrochloride form. Yield: 16.83 grams of white crystals (═ 50% of theory);

melting point: 184 ℃ and 185 ℃.

10.3.: tropenol 2-fluoro-2, 2-bis (3-chlorophenyl) acetate 4 i:

1.48 g (0.0067 mol) of bis- (2-methoxyethyl) aminosulfur trifluoride are added dropwise to 10 ml of dichloromethane and a solution of 2.09 g and 5g in 65 ml of dichloromethane at 15-20 ℃ over 20 minutes.

The mixture is stirred at ambient temperature for 20 hours, cooled to 0 ℃ and carefully mixed with thorough stirring with 80 ml of water. The mixture is then carefully adjusted to pH 8 with aqueous sodium hydrogencarbonate solution, the organic phases are separated, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over magnesium sulfate and evaporated to dryness. The hydrochloride salt precipitated out and was recrystallized from acetonitrile/diethyl ether.

Yield: 1.20 g white crystals (═ 53% of theory);

melting point: 136 and 137 ℃.

10.4.：Tropenol 2-fluoro-2, 2-bis (3-chlorophenyl) acetate-methyl bromide:

1.0 g (0.002 mol)4hThe reaction was carried out in a similar manner to example 1, step 1.3. The crystals formed were filtered off with suction, washed with dichloromethane, dehydrated and then recrystallized from methanol/diethyl ether.

Yield: 0.82 g white crystals (═ 80% of theory);

TLC: rf value: 0.14 (eluent: n-butanol/water/formic acid (concentrated)/acetone/dichloromethane 36: 15: 5);

melting point: 180 ℃ and 181 ℃.

C₂₃H₂₃Cl₂FNO₂×Br(515.25)；

It has been found that1The compounds are characterized by a variety of uses in therapy. Of particular interest are the formulae according to the invention1The compounds are preferably used as anticholinergic agents on the basis of their pharmaceutical effectiveness. Such uses include, for example, the treatment of asthma or COPD (chronic obstructive pulmonary disease). General formula (VII)1The compounds are also useful in the treatment of vagally induced sinus bradycardia and in the treatment of cardiac rhythm disorders. In general, the compounds of the present invention may also be useful in the treatment of spasticity, such as gastrointestinal spasms. Can also be used for treating urospasm and menstrual disorder. Within the above-listed indications to use the formula of the invention1The compounds are particularly important in the treatment of asthma and COPD.

General formula (VII)1The compounds may be used alone or in combination with other compounds of the formula1The effective substance is used.

General formula (VII)1The compounds may also be combined with other pharmacologically active substances as desired. In particular, beta-mimetics, antiallergic agents, platelet aggregation factor antagonists (PAF-antagonists), leukotriene antagonists, as well as corticosteroids and combinations of these active substances are included.

Can be combined with the present inventionFormula (II)1Compounds beta mimetics used in combination include compounds selected from the following list: mesoprocarbinol (bambuterol), tolbutadine (bitolterol), albuterol (carbuterol), albuterol (carbutarol), clenbuterol (clenbuterol), albuterol (fenoterol), formoterol (formoterol), paracetamol (hexoprenaline), albuterol (ibuterol), pirbuterol (pirbuterol), propachlor (procaterol), lipterol (reproterol), salmeterol (salmeterol) salfenpurol (sulphonterol), terbutaline (terbutaline), buclobutamol (tulobutanol), 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] salmeterol]Sulfonyl } ethyl]Amino } ethyl group]-2- (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl]-2-methyl-2-butylamino } ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2- (tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemic mixtures, their enantiomers, diastereomers and optionally their pharmaceutically acceptable acid addition salts and hydrates. Particularly preferred as beta-mimetics are those of the formula1The compounds are used in combination with active substances selected from the following group: procaterol (fenoterol), formoterol, salmeterol, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxy-4H-1, 4-benzoxazin-8-yl]-2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl]-2-methyl-2-butylamino } ethanol, optionally in the form of its racemic mixture, enantiomers, diastereomers and optionally its pharmaceutically acceptable acid addition salts and hydrates. Of the above beta mimetics, the compounds formoterol and salmeterol, optionally in the form of their racemic mixtures, enantiomers, diastereomers and, optionally, their pharmaceutically acceptable acid addition salts and hydrates, are of particular importance.

The preferred acid addition salts of the beta-mimetics of the present invention are preferably selected from the group consisting of the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate and xinafoate salts. Particularly preferred, in the case of salmeterol, are salts selected from the hydrochloride, sulfate and sympathofen salts, especially the sulfate and sympathofen salts. Particularly important salts according to the invention are salmeterol x 1/2 sulphate and salmeterol xinafoate. In the case of formoterol, salts selected from the hydrochloride, sulfate and fumarate salts are particularly preferred, especially the hydrochloride and fumarate salts. Of particular importance according to the invention is formoterol fumarate.

Within the scope of the invention, may be optionally combined with1The compound combination used with cortisol represents a compound selected from the group consisting of: 9-Fluorocinolone (flunisolide), beclomethasone (beclomethasone), triamcinolone (triamcinolone), budesonide (budesonide), fluticasone (fluticasone), mometasone furoate (mometasone), diclodonede (ciclesonide), rofonamide (rofleponide), GW215864, KSR 592, ST-126 and dexamethasone (dexamethasone). Preferred corticosteroids within the scope of the invention are selected from the group consisting of 9-defluoro fluocinolone, beclomethasone, fluroxypercorticosterol, budesonide, fluticasone, mometasone furoate, sildenafil and dexamethasone, wherein budesonide, fluticasoneMometasone furoate and sildenafil, in particular budesonide and fluticasone, are of particular importance. Sometimes the scope of the invention may use only steroids instead of corticosteroids. Steroids within the scope of the invention also include salts or derivatives thereof as described with reference to the relevant steroids. Examples of salts or derivatives that may be mentioned include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivaloates or furoates. The cortisol may also be present in its hydrate form if desired.

Within the scope of the invention, may be optionally combined with1Dopamine agonists to be used in combination of compounds are compounds selected from bromocriptine (bromocriptine), cabergoline (cabergolin), alpha-dihydroergocristine (alpha-dihydroergocryptine), lisuride (lisuride), pergolide (pergolide), bremipareol (pramipexol), loxindol (roxindol), lopinarol (ropinarol), talipexol (talipexol), terguride (tergurid) and pimoza (viozan). Within the scope of the invention as1The combination partners of the compounds are preferably dopamine agonists selected from the group consisting of brexpipropasol, lisuride and pimozide, especially of importance. Within the scope of the present invention, reference to the aforementioned dopamine agonists also includes the pharmaceutically acceptable acid addition salts and hydrates thereof, if present. The physiologically acceptable acid addition salts formed by the above dopamine agonists are, for example, pharmaceutically acceptable salts selected from the group consisting of salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphomethanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

According to the invention can be combined1Examples of antiallergic agents used in combination of the compounds include epinastine (epinastine), cetirizine (cetirizin), nitrogen * statin (azelastin), fexofenadine (fexofenadine), levocabastine (levocabastin), loratadine (loratadine), mizolastine (mizolastin), ketotifen (ketotifen), emedastine (emedasin), dimestine (dimentin), clemastine (clemastine), cimetidine (mibapin), ciclovir(s) (cetin), (cetirizin), cimetidine (clevidin), and the likecexchloropheniramine), dimidiaton (pheniramine), pyrimethanamine (doxylamine), chlorophenoxyamine (chlorophenoxyamine), naphthylaniline (dimehydramate), diphenhydramine (diphenhydramine), promethazine (promethazine), ebastine (ebastin), dimetaladine (meclizine). Within the scope of the invention and formula1The antiallergic agent used in combination of the compounds is preferably selected from epinastine, cetirizine, azo * statin, fexofenadine, levocabastine, loratadine, abamectin, dylamadine and mizolastine, and epinastine and dylamine are particularly preferable. The above-mentioned antiallergic agents referred to within the scope of the present invention also include pharmacologically acceptable acid addition salts in connection with their presence.

The following are formulas of the present invention1Examples of PAF antagonists for use in combination of compounds:

4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanon-1-yl ] -6H-thieno- [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepine *,

6- (2-chlorophenyl) -8, 9-dihydro-1-methyl-8- [ (4-morpholinyl) carbonyl ] -4H, 7H-cyclopenta- [4, 5] thieno- [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepine.

Is of type1The compounds are preferably used in combination with other active substances, preferably in combination with steroids or beta-mimetics, in the classes of compounds mentioned above. Especially important is the combination with beta-mimetics, especially those with long-lasting action. The invention is of1The compound is particularly preferred in combination with salmeterol or formoterol, and most preferably with formoterol.

The invention furthermore relates to pharmaceutical preparations which contain, as active substance, one or more compounds of the general formula1The compounds or physiologically acceptable salts thereof, optionally in combination with well-known excipients and/or carriers.

In use mode1Suitable formulations of the compounds include tablets, capsulesAgent, suppository, liquid, etc.

Of particular interest according to the present invention (particularly for the treatment of asthma or COPD) is the administration of the compounds of the invention by inhalation. The proportion of pharmaceutically effective compounds is from 0.05 to 90% by weight, preferably from 0.1 to 50% by weight, of the total composition. Suitable tablets are obtained, for example, by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binding agents, such as starch or gelatin, lubricating agents, such as magnesium stearate or talc, and/or agents delaying release, such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also consist of multiple layers.

Similarly, coated tablets may be prepared by coating tablet cores manufactured in a tablet-like manner with substances conventionally used for tablet coating, such as collidine or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers in order to achieve delayed release or to prevent incompatibilities. Likewise, the tablet coating may also consist of multiple layers to achieve delayed release, wherein the excipients mentioned above for the tablets may be used.

A syrup or elixir containing the active substance or composition thereof according to the invention may additionally contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar and a taste enhancer such as an aromatic substance such as vanillin or orange extract. In addition, it may also contain suspension aids or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as parabens.

The solutions are prepared in a customary manner, for example by adding isotonic agents, preservatives such as parabens, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally emulsifiers and/or dispersants, where, for example, water is used as diluent or, if desired, organic solvents are also used as solvent or cosolvent; and transferring the solution into an injection vial or ampoule or infusion bottle.

Capsules containing one or more active substances or active substance combinations can also be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and filling into gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing with carriers for this purpose, such as neutral fats or polyethylene glycols or derivatives thereof.

Examples of excipients include, for example, water, pharmaceutically acceptable organic solvents such as alkanes (e.g. petroleum fractions), oils of vegetable origin (e.g. peanut oil or sesame oil), mono-or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone), and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The administration of the formulation can be carried out by usual methods, and is preferably administered by inhalation when used for treating asthma or COPD.

For oral administration, the tablets may of course contain, in addition to the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously for tableting. In the case of aqueous suspensions, the active substances can be combined with various taste enhancers or pigments in addition to the excipients mentioned above.

The dosage of the compounds according to the invention is of course to be determined largely by the route of administration and the disease to be treated. When administered by inhalation, formula1The compounds are characterized by high efficacy, even at doses in the microgram range. Formula (II)1The compounds may also be effective for use above the microgram range, e.g., the dose is in the exempt range. In particular, when administered by a method other than inhalation, the compounds of the present invention may be administered in higher doses (e.g., 1 to 1000 mgRange, but not limited to this range).

The following formulation examples illustrate the invention without limiting its scope:

examples of pharmaceutical preparations

A) Tablet formulationEach sheet is

Active substance 100 mg

Lactose 140 mg

Corn starch 240 mg

Polyvinylpyrrolidone 15 mg

Stearic acid magnesium salt5 mg of

500 mg of

The finely ground active substance, lactose and a portion of the corn starch are mixed. The mixture is sieved, then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet granulated and dried. The granules, the remaining corn starch and magnesium stearate are screened and mixed. The mixture is compressed to produce tablets of appropriate shape and size.

B) Tablet formulationEach sheet is

80 mg of active substance

Lactose 55 mg

Corn starch 190 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Stearic acid magnesium salt2 mg of

400 mg of

The finely ground active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved and granulated with the remaining corn starch and water, the granulate is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed and the mixture is compressed to form tablets of appropriate size.

C) Ampoule solution

Active substance 50 mg

50 mg of sodium chloride

5 ml of water for injection

The active substance is dissolved in the pH of the water itself or optionally in water at pH 5.5 to 6.5 and sodium chloride is added as an isotonicity agent. The resulting solution is filtered without heat source, and the filtrate is aseptically transferred into ampoules and then sterilized and heat sealed. Ampoules contain 5 mg, 25 mg and 50 mg of active substance.

D) Quantitative aerosol

Active substance 0.005

Sorbitan trioleate 0.1

Adding fluorotrichloromethane and difluorodichloromethane in the ratio of 2: 3 to 100

The suspension is transferred to a conventional aerosol container with a dosing valve attached. Preferably 50 microliters of suspension per shot. If desired, the active substance can be dosed in higher doses (e.g. 0.02% by weight).

E) Liquid formulation (in mg/100 ml)

333.3 mg of active substance

333.3 mg formoterol fumarate

Benzalkonium chloride 10.0 mg

EDTA 50.0 mg

Hydrochloric acid (1N) to pH3.4

Such a liquid can be prepared in the usual manner.

F) Powder for inhalation

6 microgram of active substance

Formoterol fumarate 6 microgram

Lactose monohydrate to 25 mg

Powders for inhalation are produced in the usual manner by mixing the individual components.

G) Powder for inhalation

Active substance 10 microgram

Lactose monohydrate to 5 mg

Powders for inhalation are produced in the usual manner by mixing the individual components.

Claims (10)

1. General formula1Of (a) a compound

Wherein

A represents a double bond group selected from

And

X^-represents an anion having a single negative charge;

R¹and R²Identical or different, represent a group selected from methyl, ethyl, n-propyl and isopropyl, optionally substituted by hydroxyl or fluorine;

R³、R⁴、R⁵and R⁶Can be the same or different and respectively represent hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxyl, fluorine, chlorine, bromine, CN, CF₃Or NO₂；

R⁷Represents methyl, ethyl, methoxy, ethoxy, -CH₂-F、-CH₂-CH₂-F、-O-CH₂-F、-O-CH₂-CH₂-F、-CH₂-OH、-CH₂-CH₂-OH、CF₃、-CH₂-OMe、-CH₂-CH₂-OMe、-CH₂-OEt、-CH₂-CH₂-OEt、-O-COMe、-O-COEt、-O-COCF₃Fluorine, chlorine or bromine, optionally in the form of their individual optical isomers or mixtures thereof.

2. The general formula as claimed in claim 11A compound of formula (I) wherein X^-Selected from the group consisting of chloride, bromide, methosulfate, 4-toluenesulfonate and methanesulfonate.

3. The general formula as claimed in claim 11A compound which is a mixture of a compound having a structure,

wherein

A represents a double bond group selected from

And

X^- represents an anion having a single negative charge selected from the group consisting of chloride anion, bromide anion and methanesulfonate;

R¹and R²May be the same or different and represents a group selected from methyl and ethyl, optionally substituted by hydroxyl or fluorine;

R³、R⁴、R⁵and R⁶Which may be the same or different, each represent hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, fluoro, chloro or bromo;

R⁷represents methyl, ethyl, methoxy, ethoxy, CF₃Or fluorine, optionally present as individual optical isomers thereof or as mixtures thereof.

4. The general formula as claimed in claim 11A compound which is a mixture of a compound having a structure,

wherein

A represents a double bond group selected from

And

X^-represents a bromide anion;

R¹and R²May be the same or different and represents a group selected from methyl and ethyl;

R³、R⁴、R⁵and R⁶May be the same or different and represents hydrogen, methyl, methoxy, chloro or fluoro;

R⁷represents a methyl group or a fluorine group,

optionally in the form of their individual optical isomers or mixtures thereof.

5. The general formula as claimed in any of claims 1 to 41A compound of which

A represents a double bond group selected from

And

X^-represents a bromide anion;

R¹and R²May be the same or different and represents a methyl or ethyl group;

R³、R⁴、R⁵and R⁶May be the same or different and represents hydrogen or fluorine;

R⁷represents a methyl group or a fluorine group,

optionally in the form of their individual optical isomers or mixtures thereof.

6. A compound of formula as claimed in any one of claims 1 to 51Use of a compound for the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease, vagally induced sinus bradycardia, cardiac rhythm disorders, gastrointestinal spasms, urinary tract spasms, and menstrual discomfort.

7. Use according to claim 6 for the preparation of a medicament for the treatment of asthma or chronic obstructive pulmonary disease.

8. A pharmaceutical preparation comprising, as active substance, one or more compounds of the general formula according to any one of claims 1 to 51The compounds or physiologically acceptable salts thereof, optionally in combination with well-known excipients and/or carriers, are useful for the treatment of asthma or chronic obstructive pulmonary disease, vagally induced sinus bradycardia, heart rhythm disorders, gastrointestinal spasms, urospasms, and menstrual discomfort.

9. The pharmaceutical formulation of claim 8, except for one or more of the formula (la)1Chemical combinationIn addition, at least one other active substance selected from the group consisting of a beta-mimetic agent, an antiallergic agent, a platelet aggregation factor antagonist, a leukotriene antagonist and a steroid is contained.

10. Preparation general formula1A method for preparing a compound, which comprises the steps of,

a, X therein^-And R¹、R²、R³、R⁴、R⁵、R⁶And R⁷Has the definition as claimed in any of claims 1 to 5, characterized in that, in a first step, the general formula3Compound (I)

And formula2Reaction of the compounds

Formula (II)3In R³、R⁴、R⁵、R⁶And R⁷Radical as defined in any one of claims 1 to 5 and R represents chlorine or C₁-C₄-an alkoxy group,

formula (II)2In which A and R¹As defined in any one of claims 1 to 5,

to obtain the formula4Compound (I)

Wherein A and R¹、R³、R⁴、R⁵、R⁶And R⁷The compound is defined as in any one of claims 1 to 5, which is then prepared by reaction with a compound of formula R²-X compound to obtain formula1A compound which is a mixture of a compound having a structure,wherein R is²And X is as defined in any one of claims 1 to 5.